This application addresses broad Challenge Area (15) Translational Research and specific Challenge Topic, 151-AI-106: Translational research focused on high priority pathogens (influenza) and basic research focused on resistance mechanisms. Pandemic influenza remains an important threat - we are currently under a Phase 3 Alert of the WHO Global Influenza Preparedness Plan. During this phase, one of our essential tasks is to test and optimize public health intervention strategies to reduce transmission of influenza. Key among these strategies is social distancing and use of personal protective equipment including surgical masks. Unfortunately, traditional effectiveness research using empirical tests of these approaches has been mostly uninformative because of limited compliance with mask use and a requirement for very large sample sizes. Thus, we need a translational approach, rooted in basic science about how influenza is transmitted, to design and test interventions. An Institute of Medicine report, however, recently pointed out that basic data on how influenza is transmitted is lacking, posing a critical knowledge gap. Therefore, we propose to address that critical basic knowledge gap, test a specific intervention strategy, and to translate our findings into public health recommendations. We propose to use a new technology that we recently developed for biological particle collection (U.S. Provisional Patent Application No. 61/162,395) to make fundamental observations on infectious respiratory droplets in a study of 220 naturally occurring seasonal influenza cases over two influenza seasons. We will collect respiratory droplets shed by participants while breathing normally, talking, and spontaneously coughing. We will characterize the size distribution of droplets containing infectious virus and observe the impact of host factors (e.g. asthma), virus type and strain, and drug resistance on virus shedding into respiratory droplets. We will also test the effectiveness of surgical masks to limit the release of infectious droplets and whether this effect is dependent on type, strain, drug resistance, and host characteristics. We will use these basic data to examine the roles of large and small respiratory droplets and examine how the interaction of host factors and virus type impact the shedding of infectious respiratory droplets. These data will also provide a baseline for comparison to determine whether experimental human infections accurately mimic the viral shedding of people with naturally acquired, wild-type infections. Without this basic data, it will not be possible to know whether large experimental studies of influenza transmission adequately represent likely modes of transmission in the real world. Thus, this project will improve our understanding of the mechanisms of transmission for seasonal influenza;the effect of type, strain, co-infection, and drug resistance on virus release in large and small respiratory droplets;and provide evidence necessary to translate knowledge of transmission mechanisms into infection control recommendations for hospitals and the general public. PUBLIC HEALTH RELEVANCE: This project will address a critical knowledge gap about how influenza is transmitted. It will provide guidance on what public health measures are likely to be effective for limiting transmission during an influenza pandemic. The project will evaluate whether surgical masks can limit release of infectious virus from influenza patients, and provide a basis for determining when and if respirators capable of capturing fine particle aerosols are needed to protect health care workers treating influenza patients.